CYLD is a gene mutated in familial cylindromatosis and related diseases, leading to the development of skin appendages tumors. Although the deubiquitinase CYLD is a skin tumor suppressor, its role in skin physiology is unknown. Using skin organotypic cultures as experimental model to mimic human skin, we have found that CYLD acts as a regulator of epidermal differentiation in humans through the JNK signaling pathway. We have determined the requirement of CYLD for the maintenance of epidermal polarity, keratinocyte differentiation and apoptosis. We show that CYLD overexpression increases keratinocyte differentiation while CYLD loss of function impairs epidermal differentiation. In addition, we describe the important role of CYLD in the control of human non-melanoma skin cancer progression. Our results show the reversion of the malignancy of human squamous cell carcinomas that express increased levels of CYLD, while its functional inhibition enhances the aggressiveness of these tumors which progress toward spindle cell carcinomas. We have found that the mechanisms through which CYLD regulates skin cancer progression include the control of tumor differentiation, angiogenesis and cell survival. These findings of the role of CYLD in human skin cancer prognosis make our results relevant from a therapeutic point of view, and open new avenues for exploring novel cancer therapies. Cell Death and Disease (2011) 2, e208; doi:10.1038/cddis.2011.82; published online 8 September 2011
机构:Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
Bolontrade, MF
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Stern, MC
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机构:Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
Stern, MC
;
Binder, RL
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机构:Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
Binder, RL
;
Zenklusen, JC
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机构:Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
Zenklusen, JC
;
Gimenez-Conti, IB
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机构:Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
Gimenez-Conti, IB
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Conti, CJ
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Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USAUniv Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
机构:
Rockefeller Univ, Howard Hughes Med Inst, Lab Mammalian Cell Biol & Dev, New York, NY 10065 USARockefeller Univ, Howard Hughes Med Inst, Lab Mammalian Cell Biol & Dev, New York, NY 10065 USA
机构:Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
Bolontrade, MF
;
Stern, MC
论文数: 0引用数: 0
h-index: 0
机构:Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
Stern, MC
;
Binder, RL
论文数: 0引用数: 0
h-index: 0
机构:Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
Binder, RL
;
Zenklusen, JC
论文数: 0引用数: 0
h-index: 0
机构:Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
Zenklusen, JC
;
Gimenez-Conti, IB
论文数: 0引用数: 0
h-index: 0
机构:Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
Gimenez-Conti, IB
;
Conti, CJ
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USAUniv Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA
机构:
Rockefeller Univ, Howard Hughes Med Inst, Lab Mammalian Cell Biol & Dev, New York, NY 10065 USARockefeller Univ, Howard Hughes Med Inst, Lab Mammalian Cell Biol & Dev, New York, NY 10065 USA